Navigating Prader-Willi Syndrome: An Updated Guide on Causes, Diagnosis, and Treatment Outcomes

What is Prader-Willi Syndrome?

Prader-Willi syndrome is a rare genetic disorder caused by a defect of genes in the proximal arm of chromosome-15 which leads to life-threatening childhood obesity. It is associated with obesity, hypogonadism, intellectual deficits, small stature along with small hands, and feet.

A Child with Prader–Willi Syndrome

A child with Prader–Willi Syndrome

The first case of Prader-Willi syndrome was first described in a mentally impaired adolescent girl in 1887 by Langdon Down and was later described in medical literature in 1956 by Swiss doctors Andrea Prader, Alexis Labhart, and Heinrich Willi.

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What are the Signs and Symptoms of Prader-Willi Syndrome?

The presence of characteristic facial features like almond-shaped eyes, narrow bifrontal diameter, nasal bridge thin upper lip, and downturned mouth. These features are noticed soon after birth.

  • Failure to thrive and developmental delay: Children with PWS have short stature due to low levels of Human Growth Factor. Development delay is apparent when compared to normal children of similar age.
  • Weak muscles leading to floppiness (Hypotonia): These infants have a weak cry, are unable to feed, and have a limited range of motion.
  • Learning difficulties: Most children with PWS have low IQ, causing learning difficulties. They have poor short-term memory but have good long-term memory.
  • Hypogonadism and poor sexual development: Babies with PWS have abnormally small genitalia, in males, the undescended testis is a common finding. Along with physical sexual abnormalities, puberty is also delayed in these children, and lack or show minimal secondary sexual characteristics. Menarche may be delayed in females.
  • Hyperphagia leading to excessive weight gain (Obesity): Hyperphagia has been linked by various studies with excess Ghrelin (Hunger hormone) in people with PWS.
  • Mental retardation and behavioral problems: Most children with PWS show temper tantrums and stubbornness. These children usually develop some form of Compulsive behavior. Four in five cases of PWS persistently pick their skin, which leads to open scars and predisposes to infections.
  • High pain and vomiting tolerance: People with PWS have a high tolerance to pain, which can be potentially life-threatening, as serious problems may go unnoticed due to lack of pain. They have high vomit tolerance as well-meaning they can tolerate large amounts of food and inappropriate food items before they vomit; which causes them to be increasingly susceptible to food poisoning and choking.
  • Sleep disturbances: PWS associated with sleep apnea, causes difficulty sleeping at night, leading to excessive daytime sleepiness thus leading to inactivity. As a result of which obesity in children is worsened.


Prader-Willi syndrome has been described worldwide and is a genetic disorder occurring in approximately 1 in every 15,000 live births. It affects males and females equally, all races and ethnicities are equally susceptible.
It is highly unlikely for parents to have more than one child with Prader-Willi syndrome.

Cause and Pathophysiology

PWS is caused due to abnormality in the expression of genes on Chromosome 15 specifically on the long arm of chromosome 15. This abnormality can be attributed to the following :

  • Deletion of the genes on the paternal chromosome (70-80%: Most common)
  • Inactivity of the genes on the maternal chromosome (20-25%)
  • Have two copies of chromosome 15 inherited from the mother instead of one copy from each parent (maternal uniparental disomy) (1%)
  • Chromosomal translocation (<1%)
  • Imprinting center defects (Mutation) (1%)
  • PWS is the first human genetic disorder that was attributed to genomic imprinting.

The defects seen in Prader-Willi syndrome are mostly attributed to hypothalamic disorder, which may explain some typical features of the syndrome like delayed growth and hyperphagia as the hypothalamus is the center for hormone production, growth, and hunger regulation.

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Various studies have implied the role of Ghrelin in satiety defects and have found Ghrelin to be about 4-5 folds higher in people with PWS. (Ghrelin is a hormone produced by enteroendocrine cells and is also known as the Hunger Hormone)

How do you diagnose Prader-Willi syndrome?

Three sets of diagnostic criteria have been established for the diagnosis of Prader-Willi Syndrome. These are major, minor, and supportive.

Major criteria( 1 point each)

  • Neonatal and infantile hypotonia with poor suck, which improves with age.
  • Feeding problems in infancy with the need for special feeding techniques and poor weight gain/failure to thrive.
  • Excessive or rapid weight gain in children between the ages of 1-6 years.
  • Characteristic facial features such as the presence of narrow bifrontal diameter, almond-shaped eyes, narrow nasal bridge, and down-turned mouth (3 or more required).
  • Hypogonadism—with any of the following,
    Genital hypoplasia (male: scrotal hypoplasia, cryptorchidism, female: absence or hypoplasia of labia minora and/or clitoris)
  • Delayed pubertal signs in the absence of intervention after 16 years of age (male: small gonads, decreased facial and body hair, lack of voice change female: amenorrhea/ oligomenorrhea after age 16).
  • Global developmental delay in a child less than 6 years of age; mild to moderate mental retardation or learning problems in older children.
  • Hyperphagia/obsession with food

Minor Criteria (One-Half point each)

  • Decreased fetal movement and/or infantile lethargy
  • Sleep disturbance and/or sleep apnea
  • Short stature
  • Hypopigmentation of skin
  • Small hands and feet
  • Narrow hands with a straight ulnar border
  • Esotropic and/or myopic vision
  • Defects in speech articulation
  • Skin picking habit

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Supportive Criteria (No Points)

These criteria though they don’t have points, aid in the diagnosis of the disease.

  • High pain threshold
  • Ineffective thermoregulation
  • Osteoporosis
  • Scoliosis or Kyphosis
  • Proficiency in solving jigsaw puzzles.

Based on the guidelines established by Holmes et al the diagnosis of Prader-Willi syndrome is highly likely in children younger than 3 years if they score 5 points with 3 of those coming from the major criteria.

In the case of children older than 3 years with Prader-Willi syndrome is highly likely that they score 8 points with 4 from major criteria.

➢ Testing

  • Genetic testing to confirm the diagnosis of Prader-Willi Syndrome. Almost every individual with the syndrome has an abnormality in specific areas of chromosome 15. It includes an assessment of methylation patterns in the region of PWS using Polymerase Chain Reaction(PCR). Both biological parents must be tested for the presence of asymptomatic mutations in the imprinting center. Mutation in the imprinting center is associated with high recurrence. Prenatal diagnosis can be done with FISH (Fluorescent In Situ Hybridization) after chorionic villus sampling or amniocentesis.
  • Assessment of Thyroid Function and Adrenal status of the patient: Necessary when a patient has obesity, to rule out a hypometabolic state.
  • Assessment of fasting levels of IGF-1 and IGFBP-3 to check for the presence of any hormone deficiency.
  • Measurement of Glycosylated hemoglobin in obese patients to assess for the development of Diabetes Mellitus and progression to morbid obesity.
  • Sleep study on obese patients complaining of Obstructive Sleep apnea or narcolepsy.
  • Imaging Studies:

❖ Magnetic Resource Imaging (MRI) of the head to assess hypopituitarism.
❖ individuals with Prader-Willi syndrome are at risk of pathological fractures, however high degrees of pain tolerance in these patients make it necessary to diagnose fractures to prevent stiffness and malunion of fractures.
❖ DEXA Scan: To detect complications of osteoporosis.
❖ Scoliosis Film of the vertebra.

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Differential Diagnosis of Prader-Willi Syndrome

To reach the diagnosis of PWS we need to differentiate it from other diseases which may be causing similar features:

  • Angelman Syndrome
  • Fragile-X syndrome
  • Craniopharyngioma
  • Cohen Syndrome
  • Albright Hereditary Osteodystrophy
  • Spinal Muscular Atrophy
  • Alstrom Syndrome

These conditions can be differentiated from PWS with the help of the DNA Methylation technique.

Apart from these, other genetic conditions are causing short stature and obesity which need to be ruled out:

  • Bardet-Biedl Syndrome
  • Carpenter Syndrome
  • Turner Syndrome
  • Grebe Syndrome
  • Teshler -Nicola Syndrome
  • Borjeson-Forssman-Lehmann Syndrome


There is no permanent cure for Prader-Willi syndrome currently, and the treatment of the syndrome requires a multidisciplinary approach from geneticists, endocrinologists, nutritionists, pulmonologists, and neurologists to prevent complications from PWS.

The treatment is generally directed toward symptomatic relief and problem management.

The treatment plan needs to be continuously reassessed as the child grows older as it needs changes.

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Early diagnosis and treatment of PWS can go a long way in improving their quality of life and helping them reach their full potential.

Children with PWS require proper care apart from specific symptomatic treatments. Most children can benefit from the following:

Proper Nutrition

Infants with PWS have low muscle tone consequently they are unable to breastfeed properly. A pediatrician can help by recommending special feeding methods and prescribing high-calorie diets. The use of a Nasogastric tube may be required.

Weight management

A proper diet low on calories but providing necessary nutrition is key in managing the weight of PWS in children. Supplemental vitamins and minerals are required for balanced growth. A proper diet complemented with increased physical activity helps in weight management. The child should exercise for at least 60 minutes. The exercise routine should be broken down into multiple 5- 10 minute sessions in children having decreased energy levels.

As the desire for appetite in children with PWS is high, parents need to keep strict vigilance on their eating habits, there should be proper meal times, food should be kept out of their view and no extra feeding should be done.

Hormonal Management

Human growth hormone (HGH) treatment. An endocrinologist can help decide if the baby will benefit from HGH injections. In children with Prader-Willi syndrome, it helps in facilitating growth, decreasing body fat content, and increasing muscle size, and muscle tone.

Sex hormone treatment. Children with PWS have a very low sex hormone level, requiring hormone replacement therapy (Testosterone for males; estrogen and progesterone for females). HRT begins as the child approaches puberty. Apart from raising hormonal levels, it helps also prevent bone thinning. Orchidopexy may be required for Cryptorchidism (Undescended testis).

Sleep disturbance management

Treating sleep disturbances related to PWS can improve daytime sleepiness and behavioral issues in children.

Other therapies

    • Physical therapy to improve movement skills and strength.
    • Speech therapy to improve their verbal skills.
    • Occupational therapy to learn the skills required in day-to-day life.
    • Developmental therapy to learn behaviors and social skills appropriate to the child’s age.

Behavior management

Strict parenting is required to keep the behavior in check, especially concerning food, to prevent over-eating; a proper diet plan needs to be formulated. Calmness is required while dealing with children showing temper tantrums- the situation should be deflated as soon as possible by engaging the child in another topic. Medication may be required in some cases.

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Mental health care

A psychologist or a psychiatric consultation may be required to address obsessive-compulsive disorders, skin picking, or mood disorders in children with PWS. The child’s nails should be trimmed so that they do not develop cellulitis or other skin infections as a result of constant skin picking; any cases of skin infection should be treated immediately using antibiotics.

Most people with Prader-Willi syndrome will need specialized care and supervision throughout their lives for continuous consultation with the doctor is required to transition medical care to adulthood.


In cases of severe skin and pinching and psychoses, anti-depressants or anti-psychotics can be helpful. SSRIs are the antidepressants of choice. These drugs however come with associated risks, so they are generally avoided below the age of 18. Cognitive-behavioral therapy may be required in some cases. It is a talking therapy that helps to change the way the patient thinks and behaves to modify unhealthy behavioral patterns.


Patients with Prader-Willi syndrome are at risk of developing the following complications:

  • Osteoporosis and pathological fractures.
  • Obesity due to increased eating and lack of hormonal control secondary to pituitary defect leading to hypometabolism. Complications related to morbid obesity are the leading common cause of death in people with PWS.
  • Hip dysplasias
  • Sleep apnea: Patients with Prader-Willi syndrome have a defect in central control of the respiratory drive.
  • Cor- pulmonale
  • Diabetes Mellitus (DM-II)
  • Neoplasias: PWS is rarely associated with the following neoplasias
    ❖ testicular neoplasia
    ❖ Wilms tumor
    ❖ multiple endocrine neoplasias [MEN1]
    ❖ Leukemia


People with PWS, who receive early treatment usually have a normal lifespan and can function in a group home setting, and perform vocational work.

People with PWS, having normal IQ can expect to accomplish many of the things their peers do. However, each person requires lifelong support from the people involved to lead an independent life.

Complications due to morbid obesity and psychological issues can affect the quality of life and sometimes shorten life expectancy in patients with PWS.

Read Also: University of Connecticut Reverses Prader-Willi Syndrome in Lab by Restoring Silent Genes

Recent Advances 

Scientists worldwide have been working on finding a permanent cure and improving the quality of life by reducing complications for PWS by carrying out various research worldwide.

Livoletide is being monitored as a drug to reduce ghrelin and consequently hyperphagia and obesity.

A randomized, double-blind placebo-controlled study conducted in 2019 in 47 adults who took 3-4 mg of Livoletide once a day for two weeks, reported a significant decrease in food-related behaviors as compared to people who were given a placebo.


NHS. (2021, January 28). Prader-Willi syndrome: A rare genetic condition with physical symptoms, learning difficulties, and behavioural challenges. Retrieved September 23, 2023, from

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